The activity of the hypothalamo-pituitary-adrenal system is regulated by negative feedback inhibition by glucocorticoids. The goal of this project is to determine the effect of time as a variable in controlling the magnitude of subsequent ACTH and corticosteroid responses to stress by prior increases in corticosteroids. The ACTH responses to stress (hypoglycemia) or injection of ovine CRF will be compared in dogs at various times after infusion of a physiologic dose of corticosteroids, and at a single time after infusion or injection of various physiologic doses of corticosteroids, to determine the effect of time interval, and to compare the effects of corticosteroid concentration and integrated (total) corticosteroid dose (concentration x time) on subsequent ACTH responses. The effect of total and free corticosteroid concentration will also be examined. The effect of stimuli and corticosteroid feedback inhibition on the temporal pattern of ACTH secretion will also be examined by looking at frequency and amplitude of pulsatile secretion of ACTH under basal conditions, during stimulation by hypoglycemia, feeding, or adrenalectomy, and when stimulated secretion is inhibited by infusion of corticosteroids. The results of these experiments will establish the interactions between time and corticosteroid concentration in control of ACTH and are essential to constructing mathematical or conceptional models of the pituitary-adrenocortical control system.